Study Objectives. To determine the pharmacokinetic and pharmacodynamic rationale for the optimum regimen of rabeprazole in the treatment of Helicobacter pylori infection in patients who are ...cytochrome P450 (CYP) 2C19 poor metabolizers or extensive metabolizers.
Design. Prospective, multiple‐dose pharmacokinetic and pharmacodynamic study.
Setting. University‐affiliated medical center in Taiwan.
Subjects. Twelve healthy volunteers (aged 20–30 yrs) who were identified as CYP2C19 poor metabolizers (six subjects) or extensive metabolizers (six).
Intervention. Each subject received rabeprazole 20 mg twice/day for 3 consecutive days and once/day on the fourth day.
Measurements and Main Results. Pharmacokinetic and pharmacodynamic parameters were compared between CYP2C19 poor and extensive metabolizers on day 1 and day 4 of dosing. The mean ± SD values of area under the concentration‐time curve of rabeprazole and rabeprazole thioether were significantly higher in poor metabolizers than in extensive metabolizers on day 1 (5357 ± 883 vs 1131 ± 512 ng·hr/ml and 1703 ± 432 vs 561 ± 358 ng·hr/ml, respectively; p<0.001) and on day 4 (5601 ± 669 vs 1619 ± 778 ng'hr/ml and 1914 ± 378 vs 511 ± 360 ng·hr/ml, respectively; p<0.001). However, no significant difference was noted between day 1 and day 4 of dosing within the same genotype groups. Only CYP2C19 poor metabolizers had significantly higher plasma gastrin levels on day 4 compared with those levels on day 1 (p<0.05). The pharmacokinetic‐pharmacodynamic relationship of rabeprazole appears to be time dependent.
Conclusion. The pharmacokinetic and pharmacodynamic data suggest that CYP2C19 poor metabolizers might be subject to advantageous conditions, especially after day 4, for treating H. pylori infection with rabeprazole.
Whether naloxone may modulate energy metabolism and endogenous antioxidant enzyme activities in ischemic cortex was studied. Cerebral ischemia/reperfusion (I/R) was produced by occluding two common ...carotid arteries and the right middle cerebral artery for 90 min followed by reperfusion in anesthetized Sprague-Dawley rats. Both pre-treatment (0.03 or 0.3 mg) and post-treatment (0.3 mg) of naloxone by intracerebroventricular infusion significantly reduced cortical infarct volumes. Pre-treatment with 0.03 mg reduced ischemia-induced suppression of extracellular pyruvate level and enhancement of lactate/pyruvate ratio as well as cerebral I/R-induced increases of endogenous catalase, glutathione peroxidase, and manganese superoxide dismutase activities. In conclusion, neuroprotective effects of naloxone in terms of reducing brain infarction involve attenuation of the disturbance of cellular functions following cerebral I/R via restoration of mitochondrial activities or energy metabolism.
Abstract
Ferroelectric materials provide a new pathway to convert thermal energy into electricity based on the pyroelectric effect. How to modulate the pyroelectric property of ferroelectric ...materials through UV–light is still an urgent problem that needs to be solved. Here, a self‐powered sensor is demonstrated based on 0.94(Bi
0.5
Na
0.5
)TiO
3
‐0.06Ba(Zr
0.25
Ti
0.75
)O
3
nanoparticles, exhibiting high output electric performance under temperature variation and UV–light illumination conditions. Compared with a purely pyroelectric system, the corresponding current peaks of “UV–light + heating” and “UV–light + cooling” states are 88.6% higher and 37.3% smaller in the coupled system. The fabricated pyroelectric system shows excellent performance with detection sensitivities of 0.9 (heating) and 1.48 nA K
−1
(cooling) with 0.7 × 10
−3
and 0.2 × 10
−3
nA lux
−1
illuminated by 395 nm UV–light as a temperature sensor. Furthermore, a self‐powered sensor that is suitable for detecting both UV–light and temperature variations by recording the output current signals are demonstrated, which provides a basis for the development of the next generation of UV–light‐modulated ferroelectric devices.
Parenteral administration of arsenic trioxide has recently been recognized as an effective antineoplastic therapy, especially for the treatment of acute promyelocytic leukemia. Its efficacy and ...toxicity are concentration-dependent and are related to the fractions of different arsenic species and the degree of methylation. In this study, arsenic trioxide was given parenterally to rabbits as a single dose or as a daily dose (0.2, 0.6, and 1.5 mg/kg) for 30 days. The blood and organ concentrations of the arsenic species, including As(III), dimethylarsinic acid (DMA), and monomethylarsonic acid (MMA), were studied on day 1 (single-dose study), day 30 (multiple dosing study), and day 60 (reversibility study). As(III) was the major detectable arsenic species in the blood. The pharmacokinetic parameters (total clearance, area under the curve, etc.) for As(III) indicated a limit for the capacity to eliminate As(III) at the dose of 1.5 mg/kg, and were quite the same after a single dose or chronic multiple dosing. In tissues, DMA was found to be the major metabolite and the concentrations of DMA, As(III), and MMA in general increased with the dose, with the increase most significant at a dose of 1.5 mg/kg. However, normalized tissue distribution of As(III) in the kidney on day 1, but not on day 30, was nonlinear. Along with decreased levels of As(III) and increased levels of DMA, an inducible capacity for methylating As(III) to DMA after chronic dosing in kidney was suggested. The tissue concentration of DMA was highest in lung and liver, and the normalized tissue distributions in liver on day 30 were nonlinear, suggesting a limit in eliminating DMA after a chronic high load of As(III). Tissue concentrations of As(III), DMA, and MMA in bladder increased dramatically after chronic dosing. However, after washout for 30 days, As(III), DMA, and MMA were all undetectable in bladder and liver. However, As(III) in hair and low levels of DMA in lung, kidney, heart and hair were still detected. In conclusion, in rabbits we found a similar pharmacological profile after a single dose or chronic multiple dosing of parenteral arsenic trioxide, with a limiting metabolizing capacity at a dose of 1.5 mg/kg. Tissue accumulation of arsenic species, mainly DMA, and its reversibility after washout were tissue-selective. The potential for late toxicities of arsenic trioxide in organs with a significant tendency for arsenic accumulation with low reversibility should be closely monitored.
A simple and convergent synthetic strategy used to increase the diversity of the carbodicarbene ligand framework through incorporation of unsymmetrical pendant groups is reported. Structural analysis ...and spectroscopic studies of ligands and their Rh complexes are reported. Reactivity studies reveal carbodicarbenes as competent organocatalysts for amine methylation using CO2 as a synthon. A unique BH‐activated boron–carbodicarbene complex was isolated as a reaction intermediate, providing mechanistic insight into the CO2 functionalization process.
Auf dem Weg zur Großfamilie: Eine einfache konvergente Synthesestrategie erhöht die Diversität des Carbodicarben‐Ligandgerüsts durch unsymmetrische Substitution. Die Carbodicarbene vermitteln als Organokatalysatoren die Methylierung von Aminen mit CO2 als Synthesebaustein.
To compare the effectiveness of modified automated and manual pulsed radiofrequency (RF) algorithms using internally cooled electrodes for hepatocellular carcinoma (HCC).
Seventy-seven ...treatment-naive cirrhotic patients with 102 HCC (< or =4 cm) underwent 109 sessions of ultrasound-guided percutaneous RF ablation using a 17-gauge, 20-cm-long, single internally cooled electrode. Patients were assigned alternatively: 40 patients to the modified automated algorithm group and 37 patients to the manual algorithm group. The mean tumor diameters were 2.34 +/- 0.9 and 2.25 +/- 0.7 cm in the automated and manual groups, respectively (p = 0.56). Primary technique effectiveness and local tumor progression were compared between the two groups.
More overlapping ablations (n = 112) were required in the manual than in the automated group (n = 82) to achieve similar primary technique effectiveness rates of 96.1 and 94.1%, respectively. After a mean follow-up period of 26.7 +/- 1.1 months, the local tumor progression rates at 12 and 18 months were 4 and 20% in the manual group and 12 and 24% in the modified automated group (p = 0.3). Only tumors >3 cm were independently associated with local tumor progression (odds ratio 1.25; 95% CI 1.06-2.34, p = 0.03).
The manual algorithm requires more overlapping ablations and treatment sessions in order to achieve similar primary technique effectiveness and local tumor progression rates compared with the modified automated algorithm.
Human CMV (HCMV) is an important pathogen that causes widespread diseases in immunocompromised individuals. Among the opportunistic HCMV infections, HCMV retinitis is most common in transplant ...recipients and AIDS patients. It often leads to blindness if left untreated. The question as to how HCMV infection causes retinal pathogenesis remains unresolved. Here, we report that viral immediate-early gene product 2 (IE2), but not IE1, up-regulates the Fas ligand (FasL) expression in HCMV-infected human retinal pigment epithelium cells. Increased secretion of FasL from virally infected cells into cultured medium was observed upon HCMV infection. The capability of such cell-free medium to induce apoptosis of Fas (CD95)-expressing Jurkat cells further implies that Fas-FasL interaction might mediate cell death in the lesion of HCMV retinitis. To support this idea, we observed augmented soluble FasL levels in vitreous from AIDS patients with HCMV retinitis as compared with that from AIDS patients without HCMV infection. In addition, by in situ hybridization and immunohistochemistry, we detected enhanced signals of FasL, the existence of viral IE Ags and apoptotic cells at the same sites in the lesion of HCMV-infected retina. These results strongly suggest that IE2 induction of FasL expression in human retina might be an important event that takes place in the early stage of infection and finally leads to visual loss in individuals affiliated with HCMV retinitis.
PDF
